A Closer Look at Two Aspects of AD Clinical Trials

As the Progress Report has shown, clinical trials are essential to continued progress in AD research. Clinical trials, which compare a potential new treatment with a standard treatment or with a placebo, are the primary way that researchers find out whether a promising treatment is safe and effective. Clinical trials also tell researchers which treatments are more effective than others. Some clinical trials focus on treatment strategies—helping people with AD preserve cognitive function for as long as possible, for example, or helping people with behavioral or psychiatric problems associated with AD. Other clinical trials focus on prevention strategies—using specific interventions or drugs to help people reduce the risk of developing AD in the future. Here’s a look at two critical aspects of clinical trials research.

ADCS Study Sites in 2006

Establishing the Infrastructure to Conduct Clinical Trials

In 1991, NIA launched the Alzheimer’s Disease Cooperative Study (ADCS; http://adcs.ucsd.edu), a consortium of research sites around the country. The ADCS conducts clinical trials on compounds that are not generally of interest to large pharmaceutical companies. These include drugs that are off patent, drugs that are patented and marketed for another use but may be useful in treating cognitive and behavioral symptoms of AD, and novel compounds from individual investigators or small companies without adequate resources for clinical trials. Currently, the ADCS is supporting five clinical trials.

The latest renewal of the ADCS in 2006 will support new clinical trials to test drugs for their effectiveness in slowing the progression or treating the symptoms of AD, as well as to investigate new methods for conducting dementia research. Most of the new trials will focus on possible therapies aimed at affecting beta-amyloid and tau:

• Docosahexaenoic Acid (DHA). This trial will examine whether treatment with DHA will slow decline in AD. Observational studies associate high fish consumption with reduced risk of AD in people, and studies in mouse models of AD show that dietary DHA reduces brain levels of beta-amyloid, oxidative damage associated with beta-amyloid, and neurotoxicity (see "A Healthy Diet May Be Important to Brain Health as Well as Body Health" for more on this research).
• Intravenous Immunoglobulin (IVIg). Interest in passive immunization strategies against AD is growing (see ""The Emerging Field of AD Translational Research" for more on these strategies). IVIg contains naturally-occurring antibodies against beta-amyloid, and preliminary studies have shown that IVIg may improve cognition. In addition, research has demonstrated that IVIg increased levels of anti-beta-amyloid antibodies in plasma and promoted clearance of beta-amyloid from cerebrospinal fluid. The new ADCS trial will demonstrate whether IVIg is useful clinically for treating AD.
• Lithium. The biological activity of lithium, which has been shown in animal studies to block abnormal changes in tau, is of interest to ADCS investigators. They will undertake a pilot biomarker study to see whether the drug can lower tau and beta-amyloid levels in cerebrospinal fluid and be safely tolerated in older AD patients.

Innovative Ways to Recruit and Retain Participants

One of the major limitations in conducting trials in older adults is recruiting and retaining individuals who can effectively participate in lengthy evaluations in a specialized clinic setting. Many older people, particularly the very elderly, have physical, social, and health limitations that make it difficult for them to take part in research. Thus, NIA AD investigators are examining ways to make it easier for volunteers to participate in clinical research, and they are developing novel procedures and measures that can be administered at home or in other community settings:

• The GEM trial. Extracts of leaves from the Ginkgo biloba tree are thought to have beneficial effects on brain function, especially those related to dementia and AD. This 10-year clinical trial, which began in 2000 and is co-funded by NCCAM, NHLBI, and NIA, is comparing ginkgo to placebo in people older than 75 who were cognitively healthy or who had MCI at the beginning of the trial (DeKosky et al., 2006). The study’s main goal is to determine whether ginkgo is helpful in preventing or delaying the onset of dementia, though researchers also are interested in assessing participants’ rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and causes of death. All participants have extensive neuropsychological evaluations at the beginning of the study. Each also has someone who has agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6 months. Significant cognitive decline at any visit leads to a repeat detailed neuropsychological assessment and a neurological and medical evaluation. Side effects and adverse events also are closely monitored.
  
  As with all clinical trials, recruitment was an important challenge. The researchers’ goal was to enroll about 3,000 people age 75 and older at four sites in the U.S. (Fitzpatrick et al., 2006). The investigators understood early on that recruiting participants in this age range would be difficult, and they carefully planned a systematic approach that included ways to collect data on the recruitment process. From the beginning, they tracked eligibility and refusal rates, which allowed for adjustments as needed. Study staff began their enrollment efforts by mailing 243,400 brochures about the study to potential participants. Follow-up phone calls to 14,603 households yielded 12,186 successful contacts. Out of these 12,186 people, 2,149 people were ineligible to participate because of cognitive, medical, or other reasons. Of the remaining people, 6,944 decided not to join. The end result was that 3,072 people enrolled in the study, a recruitment rate of about 25 percent based on telephone contacts made, or about 1 percent based on the initial mailing.
  
  
• ADCS Prevention Instrument Project. Investigators are designing and developing new questionnaires and other instruments that can be used to evaluate individuals’ overall cognitive functioning, memory, ability to carry out activities of daily life, and quality of life. These instruments, which are mostly self-administered, can be completed in a less time-consuming and more cost-efficient manner than was possible with previous instruments. The aim of this project is to evaluate the effectiveness of these new tests in identifying change over time and conversion to MCI or AD in cognitively healthy elderly and to compare assessments completed in the clinic (the traditional in-person method) with those completed at home. The 4-year study simulates a primary prevention trial, a type of trial that aims to prevent the development of a disease. This study has enrolled 644 healthy adults 75 years of age and older. Participants have been randomized to one of two groups, where baseline and follow-up assessments are completed at home or in the clinic. Results obtained from both venues are being analyzed to determine whether the home evaluations are equivalent to those done in the clinic. Data collection and analysis are continuing.
  
  
• Home-Based Assessment. This new ADCS study, conducted in people aged 75 and older, will further examine the development and use of home-based assessments. Three types of in-home assessment and data collection procedures are being examined: a) low-technology telephone assessment; b) a high-technology automated telephone assessment; and c) a high-technology computer assessment. Cognition, daily functioning, mood, and other factors will be evaluated in each of the methods. These innovative assessment and data collection methods will again be compared against traditional in-person methods. The findings from this study will provide information on how home-based assessments might be used in prevention trials. Such methods could significantly reduce the cost and increase the feasibility of participation in these long-term clinical trials.

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